Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in arachidonic acid cascade, plays a key role in the biosynthesis of prostaglandin E₂ (PGE₂) upon inflammatory insults. Overproduction of PGE₂ stimulates proliferation of various cancer cells, confers resistance to apoptosis of cancerous or transformed cells, and accelerates metastasis and angiogenesis. Excess PGE₂ undergoes metabolic inactivation which is catalyzed by NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In this context, 15-PGDH has been speculated as a physiological antagonist of COX-2 and a tumor suppressor. Thus, overexpression of 15-PGDH has been known to protect against experimentally induced carcinogenesis and renders the cancerous or transformed cells susceptible to apoptosis by counteracting oncogenic action of PGE₂. In contrast, silence of 15-PGDH is observed in some cancer cells, which is associated with epigenetic modification, such as DNA methylation and histone deacetylation, in the promoter region of 15-PGDH. A variety of compounds capable of inducing the expression of 15-PGDH have been reported, which include the histone deacetylase inhibitors, nonsteroidal anti-inflammatory drugs, and peroxisome proliferator-activated receptor-gamma agonists. Therefore, 15-PGDH may be considered as a novel molecular target for cancer chemoprevention and therapy. This review highlights the role of 15-PGDH in carcinogenesis and its regulation.